Citations

Amyloid neuropathy is caused by deposition of insoluble β‐pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light‐chain amyloidosis, a clonal non‐proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the TTR gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood–nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length‐dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early‐onset Val30Met ATTRv, whereas other ATTRv and light‐chain amyloidosis often present with large‐ and small‐fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone‐avid radiotracer cardiac imaging. Treatment of light‐chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5‐year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024;96:423–440

Abstract Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)‐specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US‐based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium‐based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene‐silencing therapeutics recommended as a first‐line option. Consensus is lacking on what represents “disease progression” during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy.